2-haloquinoxaline and process for preparing same



Patented Jan. 9, 1951 Z-HALDQUINOXALINE AND PROCESS FOR PREPARING SAME Frank J. Welt, Westfield, N. J., assignor to Merck .& Ca, End, Hallway, N. .I.,.a corporation of New Jersey No Drawing. Application July 3, 1946, Serial No. 681,421

6 Claims.

This invention relates to processes for preparing sulfa drugs such as sulfaquinoxaline and derivatives thereof, and particularly to an improved process for preparing the intermediate Z-aminoquinoxaline through new intermediate 2- haloquinoxalines.

The production of 2-sulfanilamidoquinoxaline (sulfaquinoxaline) and derivatives thereof through the intermediate Z-aminoquinoxaline is disclosed in a publication by Weijlard, Tishler, and Erickson, J. A. C. S., 66, 1957 (1944). According to this publication, 2-aminoquinoxaline has previously been prepared from alloxazine, either directly by cleavage with sulfuric acid or indirectly by cleavage with concentrated ammonia followed by decarboxylation of the 27 amino-3-carboxyquinoxaline thus formed. A serious drawback of this process is that alloxazine is a relatively scarce and costly material.

It 'has been discovered, inaccordance with the present invention, that Z-aminoquinoxaline can be prepared in an efficient and practical way starting with the readily available material phenylene diamine by reacting the same with a compound of the class consisting of glyoxalic acid, lower alkyl glyoxalates, and the addition product of glyoxalic acid and sodium bisulfite to form Z-hydroxyquinoxaline; converting the 2- hydroxy compound to a 2haloquinoxaline by reaction with phosphorous halides; and heating the 2haloquinoxaline with alcoholic ammonia, under pressure, to form the desired Z-aminoquinoxaline.

In carrying out the process of the present invention, o-phenylene diamine and n-butyl g'lyoxalate, or other glyoxalic compound of the class above noted, are heated together in aqueous medium and the precipitate thus formed is dissolved in dilute alkali such as 1 N sodium hydroxide, treated with decolorizing charcoal, reprecipitated by acidification as, for example, with acetic acid, removed by filtration, and dried.

A mixture of dried z-hydroxyquinoxaline and phosphorous halides such as phosphorous pentachloride and phosphorous oxychloride, or phosphorous pentabromide and phosphorous oxybromide, is heated to about 130 C. until the reaction mixture is completely liquefied, and heating is continued for about 45 minutes longer. The reaction mixture is then cooled and finally poured over ice with stirring, causing precipitation of a Z-haloquinoxaline such as Z-chloroquinoxaline or Z-bromoquinoxaline which can be purified by sublimation.

The z-haloquinoxaline is converted to 2- O-phcnylcnc Glyoxalic acid, 'Z-hydroxyquinoxaline diaminc lower alkyl glyoxalate, or g1y0xalic.acid sodium bisulli to addition product.

halogen N 2'haloquinoxeline 2-aminoquinoxaline P hospliorous halides pressure incrt solvent The following examples indicate in greater detail how procedures of the present invention are carried out, and it will be understood that these examples are given by way of illustration and not of limitation.

Example I A mixture of 6.5 g. of n-butyl glyoxalate, 5.4 g. of ophenylene diamine, and 100 ml. of water was stirred for 15 minutes and then heated at 50 C. for an additional 15 minutes. The precipitate thus farmed was taken up in 100 ml. of 1.0 N sodium hydroxide, treated with Norite (decolorizing charcoal) and the product was reprecipitated by acidification with acetic acid,

yielding 5.5 g. of Z-hydroxyquinoxaline (74.5%

yield), melting at 268-269 C.

The preparation of Z-hydroxyquinoxaline, as described in Example I, proceeds in the same Way when glyoxalic acid, the addition product or" glyoxalic acid and sodium bisulfite, or other lower alkyl glyoxalates are used in place of the 55 n-butyl glyoxalate.

Example II A mixture of 2.45 g. of Z-hydroxyquinoxaline, 3.65 g. of phosphorous pentachloride, and 12.5 ml. (about 21 g.) of phosphorous oxychloride was heated at 130 C. until all the solid had dissolved, and then for 45 minutes longer. The solution was cooled and poured slowly, with stirring, onto 106 g. of ice. The precipitated 2-chloroquinoxaline thus formed weighed 2.4 g. (87% yield) and had a melting point, after purification by sublimation, of 47.5 C.

When Z-hydroxyquinoxaline is reacted with phosphorous pentabromide and phosphorous oxybromide in accordance with the procedure described in Example II, 2-bromoquinoxa1ine is obtained in like manner.

Example III A mixture of 37 g. of 2-chloroquinoxaline and 300 m1. of methanol saturated with 36 g. of ammonia was heated under pressure at about 120 C. for about eight hours. The reaction mixture was then concentrated to dryness, yielding 31 g. of crude 2-aminoquinoxa1ine (95% yield). ethanol, the product melted at fi l-455C.

In the foregoing procedures the overall yield of 2-aminoquinoxaline, based upon o-phenylene diamine, is of the order of 46 to 50%. An important factor in providing a good overall yield is the use of phosphorous pentachloride and phosphorous oxychloride in combination. The process will work reasonably Well using either the pentahalide or the oxyhalide alone, but the use of the two phosphorous halides together gives a crude product which is cleaner and more easily purified than the product obtained by using either of the phosphorous halides alone.

The improved process of the present invention applies also to the preparation of derivatives of Z-aminoquinoxaline. Thus, by suitably varying the starting materials, the following derivatives of 2-aminoquinoxaline have been prepared: 3-methyl, G-methyl, 'I-rnethyl, 5-(or 8-) methyl, S-methoxyl, 7-methoxyl, 5-(or 8-) methoxyl, 6-chloro, 7-chloro, 5-(or 8-) chloro, 6-nitro, 'I-nitro, 6-bromo, '7-bromo, and 6-(01' 7-) car-- boxy. While these derivatives are potentially useful organic intermediates, they are not as suited as 2-aminoquinoxaline itself in the prepa- After recrystallization from benzeneration of physiologically active sulfanilamido compounds. 7

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof, and I am to be limited only by the appended claims.

I claim:

1. A compound selected from the class consisting of 2-chloroquinoxa1ine and 2-bromoquinoxaline.

2. 2-chloroquinoxaline.

3. 2-bromoquinoxaline.

4. The process that comprises heating 2-hydroxyquinoxaline with a mixture of phosphorous halides of the class consisting of mixtures of phosphorous pentachloride and phosphorous oxychloride, and mixtures of phosphorous pentabromide and phosphorous oxybromide at about 130 C. for a time sufiicient to effect reaction therebetween, cooling the reaction mixture, and recovering the 2-haloquinoxaline thus formed.

5. The process for preparing Z-haloquinoxaline which comprises reacting Z-hydroxyquinoxaline With a phosphorous halide of the class consisting of phosphorous pentachloride, phosphorous oxychloride, phosphorous pentabromide, and phosphorous oxybromide at a temperature of about 130 C. to form the corresponding 2-haloquinoxaline.

6. The process that comprises heating 2-hydroxyquinoxaline with a mixture of phosphorous pentachloride and phosphorous oxychloride at about 130 C. for a time sufiicient to eifect reaction therebetween, cooling the reaction mixture, and recovering the Z-chloroquinoxaline thus formed.

FRANK J. WOLF.

REFERENCES CITED UNITED STATES PATENTS Name Date Winnek et al. Mar. 5, 1946 OTHER. REFERENCES Gowenlock et al J. Chem. $06., 1945, 622-625. Beilstein, vol. 23, 4th edition, page 177.

Number 

2. 2-CHLOROQUINOXALINE. 